Cofactors facilitate bona fide prion misfolding in vitro but are not necessary for the infectivity of recombinant murine prions
Prion diseases, particularly sporadic cases, pose a challenge due to their complex nature and heterogeneity. The underlying mechanism of the spontaneous conversion from PrPC to PrPSc, the hallmark of prion diseases, remains elusive. To shed light on this process and the involvement of cofactors, we have developed an in vitro system that faithfully mimics spontaneous prion misfolding using minimal components. By employing this PMSA methodology and introducing an isoleucine residue at position 108 in mouse PrP, we successfully generated recombinant murine prion strains with distinct biochemical and biological properties. Our study aimed to explore the influence of a polyanionic cofactor in modulating strain selection and infectivity in de novo-generated synthetic prions. These results not only validate PMSA as a robust method for generating diverse bona fide recombinant prions but also emphasize the significance of cofactors in shaping specific prion conformers capable of crossing species barriers. Interestingly, once these conformers are established, our findings suggest that cofactors are not necessary for their infectivity. This research provides valuable insights into the propagation and maintenance of the pathobiological features of cross-species transmissible recombinant murine prion and highlights the intricate interplay between cofactors and prion strain characteristics.
Authors
- Carlos M. Díaz‐Domínguez (ORCID: https://orcid.org/0000-0002-0410-1963)
- Mariví Geijó (ORCID: https://orcid.org/0000-0002-3120-1038)
- Glenn C. Telling (ORCID: https://orcid.org/0000-0002-6294-1805)
- Joseba M. Garrido (ORCID: https://orcid.org/0000-0002-7559-0653)
- Miguel A. Pérez‐Castro (ORCID: https://orcid.org/0000-0003-2850-3470)
- Jesús R. Requena (ORCID: https://orcid.org/0000-0003-1954-4975)
- Hasier Eraña (ORCID: https://orcid.org/0000-0001-8776-4211)
- Joaquı́n Castilla (ORCID: https://orcid.org/0000-0002-2216-1361)
- Enríc Vidal (ORCID: https://orcid.org/0000-0002-4965-3286)
- Nuno Gonçalves-Anjo (ORCID: https://orcid.org/0000-0003-0586-2550)
- Manuel Sánchez‐Martín (ORCID: https://orcid.org/0000-0001-8370-1336)
- Ezequiel González-Miranda (ORCID: https://orcid.org/0000-0001-9422-7297)
- Nuria L. Lorenzo (ORCID: https://orcid.org/0000-0002-6444-6269)
- Josu Galarza-Ahumada
- Patricia Piñeiro (ORCID: https://orcid.org/0000-0002-0062-2542)
- Jorge M. Charco
- Samanta Giler
Institutions
- Ikerbasque (ES)
- Universitat Autònoma de Barcelona (ES)
- Universidad de Salamanca (ES)
- Universidade de Santiago de Compostela (ES)
- Instituto de Salud Carlos III (ES)
- Centre de Recerca en Sanitat Animal (ES)
- CIC bioGUNE (ES)
- Centro de Investigación Biomédica en Red (ES)
- NEIKER, Basque Institute for Agricultural Research and Development (ES)
- Instituto de Investigación Biomédica de Salamanca (ES)
- Colorado State University (US)
Publication Details
- Journal
- PLoS Pathogens
- Published
- 2025-01-22
- DOI
- https://doi.org/10.1371/journal.ppat.1012890
- Citations
- 8
- Primary Topic
- Prion Diseases and Protein Misfolding
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- European Commission
- Ministerio de Ciencia e Innovación
- Instituto de Salud Carlos III
- European Regional Development Fund
- Agencia Estatal de Investigación
- Interreg